Non-invasive monitoring of a constituent of a physiological fluid

ABSTRACT

For non-invasively monitoring the concentration of a substance in blood, use is made of a pickup unit, with a cavity through which a liquid is passed. The cavity is held against the skin and the concentration of the substance which has penetrated into the passing liquid is measured. The method according to the invention makes it possible to monitor non-invasively and continuously the extent to which various low-molecular, water-soluble substances are present in the body of a human or an animal. Further described is an instrument for carrying out the method according to the invention.

BACKGROUND OF THE INVENTION

The invention relates to a method for non-invasively monitoring theconcentration of a substance in a fluid produced by a human or ananimal, in which method a pickup unit is held against the skin and theamount of substance received in the pickup unit is measured.

Such a method is disclosed in Japanese patent application 61-25541. Thisknown method is intended for measuring the glucose concentration in theblood, in particular in patients with diabetes.

It is observed that hereinafter the term "patient" is understood to meana human or an animal in general, whether healthy or ill.

According to this known method, a glucose oxidase enzyme is immobilizeddirectly behind a cellulose membrane which has a good permeability towater and substances dissolved therein. Behind that, a limiting membraneis provided, which arrests reduced substances but allows water, hydrogenperoxide and salts to pass therethrough. Behind this membrane, hydrogenperoxide is detected with a platinum electrode.

The glucose oxidase enzyme produces hydrogen peroxide and an acid,depending on the amount of glucose which has passed through thecellulose membrane. The acid is arrested by the limiting membrane, butthe hydrogen peroxide is allowed to pass. Through the electrode flows anelectrical current which is dependent on the amount of hydrogen peroxidewhich has entered the fluid. Thus, on the basis of the currentintensity, the amount of glucose which has passed through the cellulosemembrane can be determined. The amount of glucose which has passedthrough the cellulose membrane, in turn, is dependent on the glucoseconcentration in the blood. Thus, this concentration can be monitoredcontinuously and without

A drawback of this known method is that it is only suitable formonitoring the glucose concentration.

In other known methods where, on the basis of the substance penetratingthrough the skin, the extent to which that substance is present in thebody is measured transcutaneously, that substance is accumulated over agiven period. An interruption of the accumulation or an unreliableperiod within the time period of the accumulation is then disastrous forthe reliability of the results obtained after that interruption orunreliable period.

SUMMARY OF THE INVENTION

The object of the invention is to provide a method which is alsosuitable for non-invasively monitoring the concentration of otherlow-molecular, water-soluble substances.

According to the present invention, this object is realized in that, ina method of the type described in the opening paragraph hereof, liquidis passed through the pickup unit continuously and the concentration ofthe substance is measured in the liquid stream, downstream of the pickupunit.

In the method according to the invention any accumulation of thesubstances received in the liquid is avoided in that the liquid iscontinuously refreshed. As a result, regardless of the duration of themonitoring, as long as the concentration of the substance in question,for instance in the blood, remains within a given range, theconcentration in the liquid of the substance whose concentration in theblood is to be monitored will remain within a corresponding, relativelylimited range. This range can moreover be influenced by appropriatelychoosing the replacement rate of the liquid in the cavity. Thus, theconcentration of the substance in question in the liquid can be causedto remain within a range within which it can be properly measured.

Further, the concentration of the substance in question in the liquid isto a high degree directly proportional to the concentration of thatsubstance in the blood. Thus, the course of the concentration of thesubstance in the liquid provides in a simple manner an indication of thecourse of the concentration of that substance in the blood. Interruptionof the measurements or periods within the time duration of themonitoring which are considered unreliable have no or hardly any adverseinfluence on the reliability of the results obtained after thatinterruption or unreliable period.

The method according to the invention is suitable inter alia formonitoring the concentration in the blood of substances which are notremoved from the liquid during measurement. In principle, theconcentration in the blood of any low-molecular substance can bemonitored and the method according to the invention can be used formonitoring the concentration of both metabolic substances andmedicaments.

The method according to the invention is suitable not only for measuringthe concentration of substances in the blood but also for measuring theconcentration in other fluids in the body or secreted by the body, suchas sweat or epidermal moisture.

A further advantage of the method according to the invention is that thesubstance to be measured itself penetrates into the liquid and can bedetected. As a consequence, a retarding, interfering and complicatingintermediate conversion step such as the step utilized in the knownmethod, whereby hydrogen peroxide is produced by the glucose oxidaseenzyme, can in most cases be omitted.

The invention can further be embodied in an instrument adapted for theapplication of the method according to the invention, and in a pickupunit for use in a device according to the invention.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is an embodiment of the pickup unit for use in a device accordingto the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The exemplary embodiment of a pickup unit as shown in longitudinalsection in the drawing, for use in an instrument for carrying out themethod according to the invention, comprises a membrane 1 and a housing2 with a cavity 3 closed off by the membrane 1. For discharging liquidlocated behind the membrane 1 and for supplying new liquid behind themembrane 1, the pickup unit comprises a supply conduit 4 and a dischargeconduit 5, respectively. Means for measuring the concentration of asubstance in liquid discharged from the cavity 3 are not shown. Thesemay for instance be arranged at a distance from the pickup unit in thedischarge conduit 5.

For carrying out the method according to the invention, the membrane 1of the pickup unit is positioned and retained against the skin of apatient. Various substances penetrate both through the skin of thepatient and through the membrane 1 and are dissolved in the liquidpassing behind and along the membrane 1 through the cavity 3. The liquidis discharged from the cavity 3 and new liquid is supplied, whilst insimilar manner substances originating from the blood penetrate into andare dissolved in the new liquid. The concentration of the substance orsubstances whose concentration in the blood is to be monitored is alwaysmeasured in the discharged liquid.

Because in the method according to the invention the liquid in thecavity 3 is continuously replaced, no excessive accumulation ofsubstances which have passed through the mebrane 1 occurs, even if theduration of monitoring is prolonged. As a result, regardless of theduration of monitoring, as long as the concentration of the substance inquestion in the blood remains within a given expectable range, theconcentration in the liquid of the substance whose concentration in theblood is to be monitored, will remain within a corresponding, relativelylimited range. This range can moreover be influenced by appropriatelychoosing the replacement rate of the liquid behind the membrane 1 inrelation to the effective area of the membrane 1. Thus, theconcentration of the substance in question in the liquid can be causedto remain within a range within which it can be properly measured.

Further, the concentration of a substance can be monitored continuouslywithout entailing any additional delay of the observation owing to thenecessity of waiting for a measuring interval to elapse.

A further advantage of passing the liquid along the membranecontinuously is that the liquid behind the membrane is kept movingcontinuously, which improves the mixing of the substances in the liquidwhich have penetrated into the cavity 3.

Because accumulation of substances in the cavity 3 is limited, themethod according to the invention is suitable for monitoring theconcentration in the blood of substances which are not removed from theliquid during measurement. Moreover, it is possible to measure theconcentration of several substances simultaneously using a single pickupunit by measuring the concentration of several substances in the liquid.For that purpose, it is for instance possible to arrange sensors ofseveral measuring means in the discharge conduit 5. By arranging thesensors in the discharge conduit any problems with regard to space,which would occur upon their arrangement in the cavity 3, are solved.

The measured concentration of the substance in the liquid is to a highdegree proportional to the concentration of that substance in the bloodsome time prior to the time of measurement of the concentration of thatsubstance in the liquid. The duration of that time is determined by theaverage time which it takes a particle of that substance to move fromthe blood stream to the means for determining the concentration in thedischarged liquid.

Because the liquid behind the membrane is continuously replaced and theconcentration in this liquid is measured after it has been discharged,the reliability of measuring results is not influenced by interruptionsof the measurement or temporarily unreliable periods during the periodof monitoring.

A further advantage of the method according to the invention is that thesubstances to be measured themselves penetrate into the liquid,whereafter that liquid is discharged and the concentration of thosesubstances in the discharge liquid is measured. This makes it possible,in most cases, to dispense with a retarding, interfering andcomplicating intermediate conversion step. The concentration in theliquid of lactate, ethanol and glucose can for instance be measured bymeans of measuring methods which are known per se for microdialysis,such as lactography for following the lactate concentration, detectingNADH or NADPH produced by enzymes for following the concentration ofethanol and glucose, and detecting H₂ O₂ for following the cholineconcentration. Such measuring methods are for instance known from"On-line real time monitoring of extracellular lactate, ethanol, glucoseand choline, using microdialysis and enzyme reactors" by Korf et al.(1991) in "Microdialysis in the Neurosciences" T. E. Robinson and J. B.Justice (eds.), Elsevier Science Publishers B.V. 1991 and in "Continuousmonitoring of the extracellular lactate concentration by microdialysisfor the study of rat muscle metabolism in vivo", by De Boer et al.(1991) in the European Journal of Physiology, 419: 1-6, whichpublications are hereby referred to. The concentration of somesubstances can be monitored directly in electrochemical manner.

Because the means for supplying and discharging the liquid areconstructed as supply and discharge conduits 4 and 5 connecting to thecavity 3, liquid can be continuously passed along the membrane 1 in asimple manner. The concentration of a substance can be measureddownstream of the cavity 3 in the liquid stream.

The cavity 3 is constructed as a groove in the housing 2 and forms achannel, one end thereof connecting to the supply conduit 4 and theother end connecting to the discharge conduit 5. This makes it possibleto manufacture the housing 2 with cavity 3 in a simple manner. Further,as a result, the cavity has a small volume, which in turn isadvantageous for a fast reaction of the concentration in the liquid tothe supply of substances through the membrane 1. Because the channel iselongated in the direction of transport, comparatively little mixingoccurs in the direction of flow, which is advantageous for the measuringsensitivity.

The groove of the cavity 3 preferably has a width which is greater thanits depth. As a result, a relatively large effective passage area incontact with the skin is obtained and little mixing of the liquid isrequired to obtain a homogeneous distribution over the cross-section ofthe channel-shaped cavity 3, of the substances which have passed throughthe membrane 1 into the liquid.

The means for measuring the concentration of a substance in liquiddischarged from behind the membrane 1 are preferably arranged formeasuring the concentration in the discharge conduit 5. Thus, a fastreaction of the measured value to changes in the concentration in theliquid is obtained. Moreover, as a consequence, the measuring methods asdescribed hereinabove can be employed, which methods are particularlysuitable for the continuous measurement of concentrations in a flowingliquid.

The housing 2 comprises a base body 6 and a cap 7, the membrane 1 beingclamped between the base body 6 and the cap 7. In this way, in a simplemanner provisions have been created for fixing the membrane 1. Themembrane can be removed in a simple manner to replace it by a newmembrane. It is desirable to replace the membrane after each use becauseprotracted intensive contact of the membrane with the skin ofconsecutive patients would involve a substantial risk of contaminationof a patient by a preceding patient.

On the side opposite the membrane 1, the pickup unit is provided with acover 10 with apertures for the supply and the discharge conduits (4 and5, respectively).

The cap 7 and the base body 6 can be readily cleaned and optionallysterilized. The base body 6 comprises a circumferential groove in whichrests an O-ring 8. When the cap 7 is arranged over the base body 6, thisO-ring 8 provides a seal between the cap 7 and the base body 6. The cap7 is provided with an opening through which projects a portion of thebase body 6 that comprises the cavity 3. The membrane 1 rests inter aliaagainst this portion of the base body 6, so that in use the portion ofthe membrane 1 that is located in front of the cavity 3 is reliablypressed against the skin.

The pickup unit is provided with a thermostatically controlled source ofheat 9. The source of heat 9 can for instance comprise a resistor asenergy converter and a temperature-dependent semiconductor asthermostat. The base body 6 is preferably made from a material thatconducts heat well, such as aluminum or silver. Examples of suitablematerials for other parts of the housing 2 include synthetic material oraluminum.

By means of the source of heat 9, the skin can be heated to a constanttemperature in the region of the membrane 1. According as the skin iswarmer, capillary loops under the skin open up further and more arterialblood flows through them, which promotes the penetration of substancesfrom the arterial blood through the skin. By heating the skin to aconstant temperature, this effect can be promoted and controlled, whichpromotes the reliability of the relationship between the substancespenetrating through the skin and the concentrations thereof in thearterial blood.

To render the skin rich in blood, on the one hand, and to avoid burns,on the other, the skin in the region of the membrane is preferablyheated to a temperature between 40° and 45° C. In most cases, atemperature of 42° C. offers the best compromise.

For measuring the concentration of an acid, such as lactate, the liquidis preferably passed through the cavity 3 at a rate of flow between0.025 and 15 μl/min per mm² of passage area of the cavity, proximal tothe skin. Good results are for instance obtained when a cavity of adepth of 0.1 to 0.2 mm, a width of 0.5 mm and a length of 8 mm is usedand the rate of flow of liquid passed through the cavity 3 is approx. 10μl/min. Because the cavity is wider than its depth, at a given volume ofthe cavity a relatively large effective passage area is obtained andrelatively little mixing of that liquid is necessary to obtain ahomogeneous distribution within the liquid of substances which havepassed through the membrane.

A rate of flow similar to that for measuring the concentration of anacid, such as lactate, is preferred for measuring the concentrations ofmore lipophilic substances, such as ethanol.

For measuring the concentration of hydrophilic substances, such asglucose, the liquid is preferably passed through the cavity at a lowerrate of flow, viz., between 0.025 and 15 μl/min per mm² of passage areaof the cavity proximal to the skin. In the case of a pickup unit with aneffective membrane area as described hereinabove, a very suitable rateof flow is for instance 2.5 μl/min.

Prior to measurement, the skin is preferably treated by applying asticky material thereto at least once and subsequently stripping thisfrom the skin. This technique is known by the name of "cellulosestripping" and for instance described in "Transepidermal potassium ion,chloride ion and water flux across delipidized and cellophane tapestripped skin" by Lo et al. in Dermatologica, 1990.

According to this technique, the horny layer of the epidermis of theskin is partly removed, so that the barrier action of the skin isreduced. In the case of glucose and alcohol, for instance, this yieldsan increase of the flow of substances passing through the skin by afactor of between 5 and 20. This makes it possible, utilizing arelatively small passage area of the cavity 3 proximal to the skin and arelatively high replacement rate of liquid, to yet obtain concentrationsof the substance(s) to be monitored in the liquid that fall within arange within which they can be properly measured. Further, through thereduced barrier action of the skin, the influence of this action on theamounts of substances penetrating into the liquid is limited, which isadvantageous for the predictive value of the measured concentration(s)of that substance or those substances in the liquid.

It is observed that, if so desired, other methods for limiting thebarrier action of the skin can be used as well, such as cleansing theskin with the aid of a fat-dissolving and/or abrasive substance or bythe use of penetration-promoting agents such as Dimethyl Sulfoxide(sometimes referred to as DMSO) or Laurocapram (available under thebrand name Azone).

The liquid which is used is preferably a physiological liquid. Thisprovides the advantage that the concentration of virtually any substancecapable of passing through the skin can be measured therein.

The pickup unit can for instance be fitted against a dorsal part of thelower arm. Depending on the objective of the measurements, the membranecan naturally be arranged against another part of the body. Prior to thearrangement of the pickup unit, a surface of, for instance, 2×2 cm ofthe skin is treated by repeatedly sticking a self-adhesive foil to it.In the pickup unit, for instance a cellulose membrane of a thickness of25 μm can be arranged. Such a membrane is commercially available, forinstance from A. H. Thomas Co. in Philadelphia, Pa., USA. The pickupunit with the membrane is subsequently fitted against the skin. For thatpurpose, it is for instance possible to use a double-sided self-adhesivetape. This is commercially available, for instance from Draeger inZoetermeer, The Netherlands.

After the pickup unit has been fitted as described hereinabove, it ispreferably heated and physiological liquid is passed through the pickupunit, the concentration of one or more substances in the liquid beingmeasured downstream of the pickup unit. If, in addition to the variationin the concentration, the absolute concentration of a substance in theblood is to be monitored as well, preferably the ratio between theconcentration of that substance in the liquid and that in the blood isestablished by taking one or more blood samples and assaying theconcentration of that substance in that blood sample. The fact is thatalthough this ratio has been found to be substantially constant for mostsubstances for a particular individual, it may vary from one person toanother.

If the pickup unit is heated, it should be moved after 6-8 hourintervals, so as prevent skin burns.

The invention can for instance be used for monitoring the lactateconcentration in the blood of patients who are seriously ill, so as toavoid repeated venal puncture, for monitoring the glucose concentrationin the blood of new-born babies in intensive care, or for non-invasivelymonitoring arterial concentrations, such as the lactate concentrationwithin the framework of sports physiology.

The invention can further be used for continuously monitoring theconcentration of a medicament in a patient. On-line monitoring evenmakes it possible to administer medicament automatically upon a decreaseof concentration, so as to keep the concentration at a given level andto minimize temporary overdosing with any associated additional harmfulside-effects.

The use of the membrane 1 is advantageous because thereby in a simplemanner a reliable seal of the cavity 3 is obtained, so that the liquidpassed therethrough cannot leak away. Further, through the use of themembrane 1, the skin is to a lesser extent subject to contact with theliquid, which is advantageous in particular in the case of measurementsover very long periods of time. Further, through the choice of asuitable membrane, a selection of substances penetrating into the cavity3 can be obtained. Finally, through the membrane 1, contamination ofdownstream parts of the measuring instrument according to the inventioncan be avoided.

It is also possible, however, to arrange for the cavity 3 to bound theskin directly without interposition of a membrane. In that case, nomembrane is required, so that costs are saved, and the amount ofsubstances penetrating into the cavity is generally larger than in thecase where a membrane is provided between the cavity 3 and the skin, sothat these substances will normally be easier to measure. The use of apickup unit without membrane 1 is particularly attractive ifmeasurements of relatively short duration are involved, where a shortreaction time is desired (and therefore a high replacement rate) and/orwhere it is problematic to obtain sufficiently high concentrations ofthe substance to be measured in the liquid passed through the cavity 3,if a membrane 1 is used.

We claim:
 1. A method for non-invasively monitoring the concentration ofa substance in a liquid produced by a human or an animal, comprisingsteps of holding a cavity of a pickup unit against the skin, measuringthe amount of substance received in the pickup unit, continuouslypassing a liquid stream through the pickup unit and measuring theconcentration of the substance in the continuous liquid streamdownstream of the cavity.
 2. A method according to claim 1 comprising,prior to measurement, treating the skin by applying an adhesive materialthereto at least once and subsequently stripping this from the skin. 3.A method according to claim 1 comprising, heating skin in the region ofthe cavity to a constant temperature.
 4. A method according to claim 3,wherein said temperature is between 40° and 45° C.
 5. A method accordingto claim 1, wherein the liquid is a physiological liquid.
 6. Aninstrument for carrying out the method according to claim 1, comprisinga cavity to which connect a supply and a discharge conduit, means forpassing a liquid stream through the cavity, and means located downstreamof the cavity, for measuring the concentration of a substance in theliquid stream in said discharge conduit.
 7. An instrument according toclaim 6, wherein the cavity is designed as a groove and forms a channelin the condition where it is closed off by a membrane, one end of saidchannel connecting to the supply conduit and the other end connecting tothe discharge conduit.
 8. An instrument according to claim 7, whereinthe groove has a width greater than its depth.
 9. An instrumentaccording to claim 6, wherein the pickup unit comprises athermostatically controlled source of heat.
 10. An instrument accordingto claim 6, wherein the cavity is designed as a groove and forms achannel in the condition where it is closed off by the skin, one end ofsaid channel connecting to the supply conduit and the other endconnecting to the discharge conduit.
 11. A method for non-invasivelymonitoring the concentration of a substance in a liquid produced by ahuman or an animal by a pickup unit comprising a cavity bounded by amembrane, comprising the steps of holding the cavity of the pickup unitagainst the skin so that the membrane is against the skin, measuring theamount of substance received in the pickup unit through the membrane,continuously passing a liquid stream through the pickup unit andmeasuring the concentration of the substance in the liquid streamdownstream of the cavity.
 12. An instrument for carrying out the methodaccording to claim 11, comprising a cavity to which connect a supply anda discharge conduit, means for passing a liquid through the cavity, andmeans located downstream of the cavity, for measuring the concentrationof a substance in the liquid stream, wherein the cavity is closed off bythe membrane.
 13. An instrument according to claim 12, wherein the meansfor measuring the concentration of a substance in the liquid streamdownstream of the cavity is arranged for measuring the concentration inthe discharge conduit.
 14. A pickup unit for use in an instrumentaccording to claim 12, comprising a cavity, to which connect a supplyand a discharge conduit and a contacting surface around the cavity to beheld against the skin in its entirety, wherein the cavity is closed offby a membrane.
 15. An instrument according to claim 12, wherein thecavity is designed as a groove and forms a channel in the conditionwhere it is closed off by the membrane, one end of said channelconnecting to the supply conduit and the other end connecting to thedischarge conduit.
 16. An instrument for carrying out the methodaccording to claim 11, comprising a cavity to which connect a supply anda discharge conduit, means for passing a liquid through the cavity, andmeans located downstream of the cavity, for measuring the concentrationof a substance in the liquid stream, wherein the cavity is closed off bya membrane, and wherein the pickup unit comprises a base body and a cap,the membrane being clamped between the base body and the cap.
 17. Apickup unit for use in an instrument according to claim 16, comprising abase body with a cavity, to which connect a supply and a dischargeconduit, a cap, a membrane closing off the cavity and a contactingsurface around the membrane, wherein the membrane is clamped between thebase body and the cap.
 18. A method for non-invasively monitoring theconcentration of a substance in a liquid produced by a human or ananimal, comprising the steps of holding a pickup unit against the skin,measuring the amount of substance received in the pickup unit, passingliquid through the pickup unit continuously at a rate of flow between0.025 and 15 μl/min per mm² of effective area of contact with the skin,and measuring the concentration of the substance in the liquid streamdownstream of the cavity.
 19. A method according to claim 18, whereinthe concentration of an acid is measured.
 20. A method according toclaim 18, wherein the concentration of a lipophilic substance ismeasured.
 21. A method according to claim 18, wherein the concentrationof a hydrophilic substance is measured.